DE1670494C3 - Boron-containing heterocyclic compounds - Google Patents

Description

wherein R ₄ and R ₅ each represent a hydrogen atom, a methyl, ethyl or methoxy radical, a halogen atom, an acetylamino or amino group, and their alkali metal salts.

The compounds described in the main patent have, inter alia. pronounced effects compared to gram-negative ones Bacteria and against protozoa, especially against trypanosomes and plasmodia. your However, its usefulness for therapy is limited by the fact that it is particularly after oral or parental administration toxic effects occur over a longer period of time, making further use impossible do.

The present invention now relates to new boron-containing heterocyclic compounds which, in the further Processing of the task of the main patent were found. It was found, surprisingly, that the compounds of the formula

N — SO,

wherein Ri is an amino group and an acylamino group means, R2 stands for a halogen atom, a trifluoromethyl group or a lower alkyl radical, R3 is

where R is an amino group or an acylamino group, R2 is a halogen atom, a trifluoromethyl group or a lower alkyl radical, R _{3 is} a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl radical and R _{4 is} a hydrogen atom or a monovalent cation.

2. l-Hydroxy-2- (2'chlor-4'-aminophenylsulfonyl) -benzo-2,3,1-diazaborine and its salts.

Patent No. 16,70,346 relates, inter alia, to boron-containing heterocyclic compounds of the formula

OH

35

40

45

50 denotes a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl radical and R ₄ denotes a hydrogen atom or a monovalent cation, have a good effect especially against many gram-negative microorganisms, are not very toxic and do not show any toxic side effects even with long-term administration. For example, the oral administration of a daily dose of 1000 mg of l-hydroxy-2- (2'-chloro-4'-aminophenyl-sulfonyl) -benzo-2,3,1-diazaborine per kg of body weight survived for a total of 13 weeks Experimental animals (rats). Therapy attempts with the sodium salt of this substance and other compounds of the formula I gave, inter alia, oral administration very favorable values for the therapeutic indices (ie in each case the quotient of the dose lethal for 50% of the animals and the dose curative for 50% of the infected animals ). It is of particular therapeutic value that the compounds of the formula I can be used both orally and parenterally and are superior to known products with the same direction of action and breadth of application. Compared to the amikacin, there was no evidence of superiority when administered subcutaneously, but the amikacin can only be used parenterally.

From these test results it results that the compounds of formula I are valuable products for Therapy are.

The making of the new valuable connections is done by making a connection of the general formula

(III

wherein X and Y are identical or different and represent hydroxyl groups, etherified hydroxyl groups or represent halogen atoms, with a sulfonic acid hydrazide of the formula

H ₂ N-NH

(III)

where R ₂ and R _{3 have} the same meaning as above and Rü denotes an amino group, an acylamino group, a nitro group or a carboxamido group and then optionally converts R5 in a manner known per se into an amino group and the radical X into the group OR4.

The compound of the general formula II is preferably reacted with the sulfonic acid hydrazide of formula III in the presence of a solvent or suspending agent, such as. B. an alcohol, dioxane, Benzene, if appropriate at an elevated temperature. The water formed in the reaction or the thereby formed compound of the formula Y-H by azeotropic distillation with a suitable solvent, such as B. benzene, removed from the reaction mixture and thus the course of the reaction is favorable to be influenced.

_{If the radical R 5} in the compound of the formula III stands for an acylamino group, the product obtained by reacting this compound with the compound of the formula II can be converted into a compound of the formula I in which Ri stands for an amino group. that the _{acyl radical contained in R 5} by hydrolysis, preferably in an acidic medium, or by hydrogenolysis (if the acyl radical is, for example, a carbobenzoxy group, an o-nitrophenoxyacetyl radical or analogous hydrogenolytically - e.g. with catalytically activated hydrogen - separable group acts) splits off.

_{If the radical R 5} in the compound of formula III is a nitro group, this radical in the condensation product of this compound and the compound of formula II can easily be converted into an amino group by reduction with nascent or catalytically activated hydrogen.

_{If the group OR 4} in the compound of the general formula I is to stand for a hydroxyl group, but X does not stand for such a group, this substituent can easily be converted into a hydroxyl group, for example by treatment with water, optionally with heating.

Because of the hydroxyl group connected to the boron atom, the compounds of formula 1 are capable. To form salts with bases, in which case R _{4 is} a cation. For example, solutions of the salts of the compounds of formula 1 can be prepared by treating them with one or two normal sodium or potassium hydroxide, with aqueous ammonia solutions or with aqueous solutions of organic bases, such as. B. triethylamine, ethylenediamine, diethanolamine, etc. shakes for a short time

Those compounds of the formula I in which R3 represents a hydrogen atom are preferred.

If Ri in the compound of the formula I is an acylamino group, that contained therein is derived Acyl radical preferably from a lower aliphatic d. H. from one containing a lower alkyl group Carboxylic acid. However, those compounds in which Ri is not acyl> rte are particularly valuable Amino group.

The term "lower alkyl" means consistently that this radical has one to five, preferably one to contains three carbon atoms.

The following examples serve to illustrate the invention. When it was carried out, the Achieving optimal yields is of no importance. All temperature data are uncorrected.

example 1

A mixture of 149.8 g o-formylphenyl boronic acid, and 265.6 g of 2-chloro-4-acetamino-benzenesulfonic acid is added to 1 liter to 3O ⁰ C heated dimethylformamide with stirring. After stirring for 30 minutes, 1 liter of hot water is slowly added to the resulting solution (with continued stirring), then cooled and filtered. The residue is washed with methanol, air-dried and dissolved in 900 ml of hot dimethylformamide. 400 ml of hot water are added with thorough stirring, the mixture is cooled and filtered. Are thus obtained in the 253-254 ° C with decomposition melting l-hydroxy-2- (2'-chloro-4'-acetamino-phenylsulfonyl) -benzo-2,3,1-diazaborine in a AncKoiitP vnn 100 0 = 75 % of theory.

Example 2

200 g of the product from Example 1 are suspended in 2.3 liters of methanol and, after adding 800 ml concentrated hydrochloric acid heated to boiling with thorough stirring. After boiling for 30 to 35 minutes, it becomes the reaction mixture was cooled in an ice bath, stirred for a further hour and then filtered. The residue will washed well with methanol and then dried. The product is in 500 ml of hot dimethylformamide dissolved and this solution is slowly mixed with 300 ml of hot water while stirring. One lets cool filtered, the residue was washed with methanol and then dried in vacuo. You get 150g = 84% of theory l-hydroxy-2- (2'-chloro-4'-aminophenylsulfonyl) -benzo-2,3, l -diazaborine with a melting point of 256-258 ° C (with decomposition).

Example 3

A mixture of 4.8 g of 2-methyl-4-acetamino-benzenesulfonic acid hydrazide (melting point 152-153 ° with decomposition), 3.3 g of o-formylphenylboric acid and 10 ml of dimethylformamide is heated, resulting in a clear solution that still lasts for 10 Is kept hot for minutes. Then 50 ml of hot water are slowly added with stirring, the mixture is cooled, filtered, the residue is washed with water and then with methanol and air-dried. Are obtained 4g = 53% of theory of 1-hydroxy-2- (2'-methyl-4'-acetamino-phenylsulfonyl) -benzo-2,3, l- diazaborine of melting point 196-198 ⁰ C.

Example 4

50 g of the product obtained in Example 3 are with a mixture of 600 ml of methanol and Boiled 200 ml of concentrated hydrochloric acid under reflux for 20 minutes. The solution obtained becomes slow diluted with 1.5 liters of hot water while stirring and then cooled. The precipitate became after several hours Standing filtered off, washed with water and methanol and air dried. You get 23 g = 52% of theory of 1-hydroxy-2- (2'-methyl-4'-aminophenylsulfonyl) -benzo-2,3,1-diazaborine which melts at 187-188 ° C.

Example 5
45

2.7 g of 2-trifluoromethyl-4-nitro-benzolsulfonsäu: ehydrazid (melting point 103-104 ⁰ C with decomposition) and 2 g of o-formyl phenylboronic acid dissolved in 5 ml of dimethylformamide. After 10 minutes, 30 ml of hot water are slowly added to the solution, while stirring, and the mixture is then cooled. The residue is washed with water, dissolved in 10 ml of dimethylformamide and reprecipitated by adding 60 ml of water. Is thus obtained in a yield of 1.6 g = 40% of theory, at 159-160 ⁰ C melting 1-hydroxy-2- (2'-trifluoromethyl-4-nitro-phenylsulfonyl) -benzo-2,3, ldiazaborin .

Example 6

18 g of the product obtained according to Example 5 are at 50 - dissolved W) ⁰ C in 1J0 ml glacial acetic acid. Then 10 g of iron powder are added with thorough stirring and the mixture, the temperature of which rises to 70-80 °, is kept at this temperature for 45 minutes. After adding 200 ml of water, the mixture is cooled and then filtered. The residue is washed with water and then treated with 35 ml of dimethylformamide. After filtering, the filtrate is slowly added to 70 ml

added hot water and then cooled. The precipitate is filtered off and washed with water and dried. 10g = 60% of theory is obtained

l-Hydroxy-2- (2'-trifluoromethy] -4'-aminojhenyl-sulfonyl) -benzo-2,3,1-diazaborine with a melting point of 244 - 246 ° C (with decomposition).

Example 7

7.5 g of o-formylphenyl boric acid and 10 g of 2-chloro-4-nifobenzenesulfonic acid hydrazide are dissolved in 50 ml of Diinethylformarnid. After 10 minutes you give Activated charcoal is added, filtered and the filtrate is slowly mixed with 40 ml of hot water while stirring. To Cooling is filtered and the residue is dissolved in 50 ml of dimethylformamide. This solution is 40 ml hot water is added, the mixture is cooled and the precipitate is then filtered off. One receives 12 g = 82% of Theory 1-Hydroxy-2- (2'-chloro-4'-nitrophenylsulfonyl) -benzo-2,3,1-diazaborine with a melting point of 210-212 ° C.

The same product is obtained by reducing this product with iron powder in glacial acetic acid at 90-100 ° C as in example 2.

Example 8

4 g of the product obtained according to Example 5 are dissolved in 75 ml of dimethylformamide and, after the addition of Raney nickel hydrogenated at 40 ° C. under normal pressure. After the uptake of hydrogen has ended, the catalyst becomes filtered off and the filtrate concentrated to a volume of about 30 ml. 70 ml of water are added and the mixture is filtered and wash the residue well with water. The same product as in Example 6 is obtained in one yield of 3.2 g = 86.8% of theory.

Example 9

4 g of the product obtained according to Example 5 are dissolved in 300 ml of glacial acetic acid and, after addition of 5% strength Palladium carbon hydrogenated at 40 ° C. under normal pressure. After the uptake of hydrogen has ended, the catalyst becomes filtered off and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 25 ml of dimethylformamide dissolved and this solution is mixed with 75 ml of water. The same product is obtained as in Examples 6 and 8 in a yield of 3.3 g = 89.5% of theory.

Claims (1)

Patent claims: 1. Boron-containing heterocyclic compounds according to main patent 16 70 346 of the formula OR ₄ N-SO ₂ (D